Gli1 in murine lung development and differentiation

描述(由申请人提供)： 安东尼·格伯博士是一名肺部和重症监护内科医生，对发育生物学有着明确的兴趣，他是在华盛顿大学医学科学家培训项目的成员中培养出来的。他的总体职业目标是通过在学术医学中心研究发育途径和肺部疾病之间的关系，将他的临床和基础科学兴趣结合起来。这项提议旨在提供实现这一目标的框架。通过一系列特定的目标，Gerber博士将测试几个关于刺猬(HH)途径在肺中的作用的假说，HH途径是一个关键的发育控制网络。具体地说，他将探索HH调节的转录因子Gli1在肺上皮和间充质中转基因错误表达的影响。这将测试Gli1在发育中的肺中调节图案化、增殖和分化的功能。肺中HH信号的影响随时间变化的假设将通过Gli1错误表达的时间调节来检验。微阵列还将用于识别肺中HH信号的靶点，以测试不同基因亚组在不同时间对HH信号做出反应的能力；最终，将使用小鼠和细胞培养模型评估Gli1对基因激活和肺损伤的影响。这项拟议的工作与肺部疾病的相关性是基于这样一个普遍的概念，即发育途径在疾病中被激活，加上最近的具体观察结果，即HH途径在肺损伤反应中被激活，并在肺癌和肺纤维化中表达。此外，这项建议旨在补充Gerber博士之前的实验室经验，并为他提供必要的肺部发育方面的技术和智力背景，以发挥独立研究人员的作用。一个由医生和科学家组成的委员会将监督Gerber博士走向独立的过程；他的科学发展也将通过出席加州大学旧金山分校的几个系列研讨会、部门务虚会和全国会议来丰富。加州大学旧金山分校致力于学术医学事业的发展，在资助期结束时，Gerber博士将准备开始他的职业生涯，作为一名独立的内科科学家，研究活跃在肺部疾病中的发育途径。

DESCRIPTION (provided by applicant): Dr. Anthony Gerber is a pulmonary and critical care physician with a well-defined interest in developmental biology that was fostered as a member of the medical scientist training program at the University of Washington. His overall career objective is to combine his clinical and basic science interests through studying the relationship between developmental pathways and lung disease in an academic medical center. This proposal is constructed to provide the framework to achieve that goal. Through a series of specific aims, Dr. Gerber will test several hypotheses regarding the role of the hedgehog (Hh) pathway, a critical developmental control network, in the lung. Specifically, he will explore the effects of transgenic misexpression of the Hh regulated transcription factor, Gli1, in the lung epithelium and mesenchyme. This will test the hyopthesis that Gli1 regulates patterning, proliferation, and differentiation in the developing lung. The hypothesis that the effects of Hh signaling in the lung vary depending on timing will be tested using temporal regulation of Gli1 mis-expression. Microarrays will also be used to identify targets of Hh signaling in the lung to test the hyopthesis that distinct subsets of genes respond to the Hh signal at different times; ultimately the effects of Gli1 on gene activation and lung injury will be assessed using mouse and cell culture models. The relevance of the proposed work to lung disease is based on the general notion that developmental pathways are activated in disease, coupled with specific recent observations that the Hh pathway is activated in response to lung injury and is expressed in lung cancer and pulmonary fibrosis. Additionally, this proposal is designed to complement Dr. Gerber's prior laboratory experience and provide him with the requisite technical and intellectual background in lung development to function as an independent investigator. A committee of physicians and scientists will oversee Dr. Gerber's progression towards independence; his scientific development will also be enriched through attendance at several seminar series at UCSF, departmental retreats, and national meetings. UCSF is committed to the development of careers in academic medicine, and at the end of the grant period, Dr. Gerber will be prepared to embark on a career as an independent physician scientist investigating developmental pathways that are active in lung disease.